US2003119792A1PendingUtilityA1
Method of inhibiting the production and/or effects of intestinal pro-inflammatory cytokines, prostaglandins and others
Priority: Sep 28, 2001Filed: Sep 30, 2002Published: Jun 26, 2003
Est. expirySep 28, 2021(expired)· nominal 20-yr term from priority
Inventors:Manuel Roca
A61K 31/437A61P 1/00A61K 31/4188
27
PatentIndex Score
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Claims
Abstract
The present invention shows that UR-12746-S, a novel locally acting compound which combines 5-ASA (an anti-inflammatory) and UR-12715 (a PAF antagonist) through an azo link, and analogous azo derivatives of 5-aminosalicylic acid compounds are able to inhibit cytokine production (IL-8, IL-1β and TNF-α) in vitro, and are shown to have intestinal anti-inflammatory activity in vivo. Moreover, daily oral administration of azo derivatives of 5-aminosalicylic acid sodium salts are able to alleviate and/or prevent relapse of inflammatory disease induced in colitic rats. This beneficial effect is evidenced by a significant reduction in colonic myeloperoxidase activity and by a significant decrease in colonic IL-1β and TNF-α.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of ameliorating negative effects of relapse of a inflammatory bowel disease in a mammal comprising administering to a mammal having suffered from inflammatory bowel disease an effective amount of a compound of Formula I:
wherein:
the 4-hydroxy-3-carboxyphenylazo moiety can be at the 3- or 4-position of the benzene ring;
m represents 1 or 2;
R 1 represents C 1-4 alkyl or C 3-7 cycloalkyl;
a, b and c represent CR 2 , wherein each R 2 independently represents hydrogen or C 1-4 alkyl;
X represents a group of formula (i) or (ii):
wherein these groups are bound to the phenyl ring in formula I via B and Z, respectively;
A represents -CO-, -SO 2 -, -NHCO- or -OCO-;
B represents a group of formula (iii), and when A represents -CO- or -SO 2 -, B can also represent a group of formula (iv), (v), (vi) or (vii);
n represents 0, 1, 2 or 3;
p represents O or I;
R 3 represents hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, C 14 alkoxy-C 1-4 alkyl or aryl;
R 4 represents hydrogen, C 1-4 alkyl, -COOR or -CONR 5 R 6 , and when A represents -CO- or -SQ-, then R 4 can also represent -NR 5 R 6 , -NR 7 C(=O)OR 5 , -NR 7 C(=O)R 5 , -NR 7 C(=O)NR 5 R 6 or -NR7SO 2 R 5 ; or R 3 and R 4 together form a C 2-6 polyrnethylene chain;
R 5 represents C 1-4 alkyl, aryl or aryl-C 1-4 alkyl;
R 6 and R 7 independently represent hydrogen or C 1-4 alkyl;
W represents -OC(=O)-, -C(=O)-, -NR 6 C(=O)- or -SO 2 -;
R 8 represents aryl;
R9 represents C 1-4 alkyl, C 3-7 cycloalkyl, -C(=O)OR 5 , -C(=O)R 5 , -C(O)NR 5 R 6 , or-SO2R 5 ;
R 10 represents C 1-4 alkyl, C 3-7 cycloalkyl, aryl, or aryl-C 1-4 alkyl;
Z represents (CH2) q CO- or-(CH 2 ) r -q represents 0, 1 or 2;
r represents 1 or 2;
R 11 represents hydrogen or halogen;
R 12 and R 13 independently represent hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkyl-C 1-6 alkyl;
or R 12 and R 13 together form a C 2-6 polyrnethylene chain;
R 14 represents -COR 15 , -COOH, -COOR 15 , -CONR 16 R 17 , -C 1-6 alkyl-OR 15 , -C 1-6 alkyl-OC(=O)R 15 or -C 1-6 alkyl-OC(=O)NR 16 R 17 ;
R 15 represents C 1-6 alkyl, C 2-6 alkenyl, C 26 alkynyl, C 3 - 7 cycloalkyl or C 1-6 haloalkyl;
R 16 and R 17 independently represent hydrogen or any of the meanings disclosed for R 15 ;
aryl, whenever appearing in the above definitions, represents phenyl or phenyl substituted with 1, 2, 3 or 4 groups independently selected from halogen, C 14 alkyl, C 1-4 alkoxy, hydroxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 14 alkylcarbonyl, C 1-4 alkylcarbonyloxy, C 1-4 alkoxycarbonyl, C 1-4 alkylsulfonyl, C 1-4 alkylsulfinyl, C 1-4 alkylthio, or C 1-4 alkylcarbonylamino; and
the pharmaceutically acceptable salts and solvates thereof.
2 . The method of claim 1 wherein said compound is 1-[[1-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3methylbutanoyl]-4-piperidyl]methyl]- 1H-2-methylimidazole [4,5-c]pyridine sodium salt or pharmaceutically acceptable solvates thereof.
3 . The method of claim 1 wherein said compound is trans-1-[[1-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3-phenylpropenoyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine sodium salt or pharmaceutically acceptable solvates thereof.
4 . The method of claim 1 wherein said compound is 1-[[1-[[N-[[4-(4-hydroxy-3-carboxyphenylazo) phenyl] sulfonil]-N-phenylamino] acetyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine sodium salt or pharmaceutically acceptable solvates thereof.
5 . The method of claim 1 wherein said compound is [N-[4-(4-hydroxy-3-carboxyphenylazo) benzoyl]-N-[4-(1H-2-methylimidazole [4,5-c]pyridylmethyl) phenylsulfonyl]-L-leucine ethyl ester sodium salt or pharmaceutically acceptable solvates thereof.
6 . The method of claim 1 wherein said compound is [N-[4-(4-hydroxy-3-carboxyphenylazo) benzyl]-N-[4-( 1H-2-methylimidazole [4,5 -c]pyridylmethyl) phenylsulfonyl]-L-leucine ethyl ester sodium salt or pharmaceutically acceptable solvates thereof.
7 . The method of claim 1 wherein said compound is [N-[4-(4-hydroxy-3-carboxyphenylazo) benzyl]-N-[(S)- 1-isobutyl-ethoxyethyl]-N-[4-(1H-2-methylimidazole [4,5-c]pyridylmethyl) phenylsulfonamide sodium salt or pharmaceutically acceptable solvates thereof.
8 . The method of claim 1 wherein said compound is cis-1-[[1-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3-phenylpropenoyl]-4-piperidyl] methyl]-1H-2
-methylimidazole [4,5-c]pyridine sodium salt or pharmaceutically acceptable solvates thereof.
9 . The method of claim 1 wherein said compound is (Z)-2-hydroxy-5-[[4-[3-[4-[(2-methyl-1H-imidazo[4,5-c]pyridin- 1-yl)methyl]-1-piperidinyl]-3-oxo-1-phenyl-1-propenyl]phenyl]azo] benzoic acid sodium salt or pharmaceutically acceptable solvates thereof.
10 . The method of claim 1 wherein said inflammatory bowel disease comprises one or more of chronic gastrointestinal inflammation, colitis, ulcerative colitis or Crohn's disease.
11 . The method of claim 1 wherein said effective amount falls in the range of about 10 mg/kg to about 10,000 mg/kg.
12 . The method of claim 1 wherein said effective amount falls in the range of about 25 mg/kg to about 100 mg/kg.
13 . The method of claim 1 wherein said effective amount is administered at least daily, optionally in two or more divided doses.
14 . The method of claim 1 wherein said effective amount is administered daily for a period of at least 7 days.
15 . The method of claim 1 wherein said effective amount is administered daily for a period of at least 2 weeks.
16 . The method of claim 1 wherein said effective amount is administered daily for a period of at least 4 weeks.
17 . The method of claim 1 wherein said effective amount is delivered orally.
18 . A method of preventing a relapse of inflammatory bowel disease in a mammal comprising administering to a mammal having suffered from inflammatory bowel disease an effective amount of a compound of Formula I:
wherein: the 4-hydroxy-3-carboxyphenylazo moiety can be at the 3- or 4-position of the benzene ring;
m represents 1 or 2;
R 1 represents C 1-4 alkyl or C 3-7 cycloalkyl;
a, b and c represent CR 2 , wherein each R 2 independently represents hydrogen or C 1-4 alkyl;
X represents a group of formula (i) or (ii):
wherein these groups are bound to the phenyl ring in formula I via B and Z, respectively;
A represents -CO-, -SO 2 -, -NHCO- or -OCO-;
B represents a group of formula (iii), and when A represents -CO- or -SO 2 -, B can also represent a group of formula (iv), (v), (vi) or (vii);
n represents 0, 1, 2 or 3;
p represents O or I;
R 3 represents hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxy-C 1-4 alkyl or aryl;
R 4 represents hydrogen, C 1-4 alkyl, -COOR 5 or -CONR 5 R 6 , and when A represents -CO- or -SQ-, then R 4 can also represent -NR 5 R 6 , -NR 7 C(=O)OR 5 , -NR 7 C(=O)R 5 , -NR 7 C(=O)NR 5 R 6 or NR 7 SO 2 R 5 or R 3 and R 4 together form a C 2-6 polymrethylene chain;
R 5 represents C 1-4 alkyl, aryl or aryl-C 1-4 alkyl;
R 6 and R 7 independently represent hydrogen or C 1-4 alkyl;
W represents -OC(=O)-, -C(=O)-, -NR 6 C(=O)- or -SO 2 -;
R 8 represents aryl;
R9 represents C 1-4 alkyl, C 3-7 cycloalkyl, -C(=O)OR 5 , -C(=O)R 5 , -C(=O)NR 5 R 6 , or -SO 2 R 5 ;
R 10 represents C 1-4 alkyl, C 3-7 cycloalkyl, aryl, or aryl-C 1-4 alkyl;
Z represents (CH 2 ) q CO- or -(CH 2 ) r -q represents 0, 1 or 2;
r represents 1 or 2;
R 11 represents hydrogen or halogen;
R 12 and R 13 independently represent hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkyl-C 1-6 alkyl;
or R 12 and R 13 together form a C 2-6 polyrnethylene chain;
R 14 represents -COR , -COOH, -COOR 15 , -CONR 16 R 17 , -C 1-6 alkyl-OR 15 , -C 1-6 alkyl-OC(=O)R 15 or -C 1-6 alkyl-OC(=O)NR 16 R 17 ;
R 15 represents C 1-6 alkyl, C 2-6 alkenyl, C 26 alkynyl, C 3-7 cycloalkyl or C 1-6 haloalkyl;
R 16 and R 17 independently represent hydrogen or any of the meanings disclosed for R 15 ;
aryl, whenever appearing in the above definitions, represents phenyl or phenyl substituted with 1, 2, 3 or 4 groups independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonyloxy, C 1-4 alkoxycarbonyl, C 1-4 alkylsulfonyl, C 1-4 alkylsulfinyl, C 1-4 alkylthio, or C 1-4 alkylcarbonylamino; and
the pharmaceutically acceptable salts and solvates thereof.
19 . The method of claim 18 wherein said compound is 1-[[1-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3methylbutanoyl]-4-piperidyl] methyl]- 1H-2-methylimidazole [4,5-c]pyridine sodium salt or pharmaceutically acceptable solvates thereof.
20 . The method of claim 18 wherein said compound is trans-1-[[1-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3-phenylpropenoyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine sodium salt or pharmaceutically acceptable solvates thereof.
21 . The method of claim 18 wherein said compound is 1-[[1-[[N-[[4-(4-hydroxy-3-carboxyphenylazo) phenyl] sulfonil]-N-phenylamino] acetyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine sodium salt or pharmaceutically acceptable solvates thereof.
22 . The method of claim 18 wherein said compound is [N-[4-(4-hydroxy-3-carboxyphenylazo) benzoyl]-N-[4-(1H-2-methylimidazole [4,5-c]pyridylmethyl) phenylsulfonyl]-L-leucine ethyl ester sodium salt or pharmaceutically acceptable solvates thereof.
23 . The method of claim 18 wherein said compound is [N-[4-(4-hydroxy-3-carboxyphenylazo) benzyl]-N-[4-(1H-2-methylimidazole [4,5-c]pyridylmethyl) phenylsulfonyl]-L-leucine ethyl ester sodium salt or pharmaceutically acceptable solvates thereof.
24 . The method of claim 18 wherein said compound is [N-[4-(4-hydroxy-3-carboxyphenylazo) benzyl]-N-[(S)- 1-isobutyl-ethoxyethyl]-N-[4-(1H-2-methylimidazole [4,5-c]pyridylmethyl) phenylsulfonamide sodium salt or pharmaceutically acceptable solvates thereof.
25 . The method of claim 18 wherein said compound is cis-1-[[1-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3-phenylpropenoyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine sodium salt or pharmaceutically acceptable solvates thereof.
26 . The method of claim 18 wherein said compound is (Z)-2-hydroxy-5-[[4-[3-[4-[(2-methyl-1H-imidazo[4,5-c]pyridin- 1 -yl)methyl] -1-piperidinyl]-3-oxo-1-phenyl- 1-propenyl]phenyl]azo] benzoic acid sodium salt or pharmaceutically acceptable solvates thereof.
27 . The method of claim 18 wherein said inflammatory bowel disease comprises one or more of chronic gastrointestinal inflammation, colitis, ulcerative colitis or Crohn's disease.
28 . The method of claim 18 wherein said effective amount falls in the range of about 10 mg/kg to about 10,000 mg/kg.
29 . The method of claim 18 wherein said effective amount falls in the range of about 25 mg/kg to about 100 mg/kg.
30 . The method of claim 18 wherein said effective amount is administered at least daily, optionally in two or more divided doses.
31 . The method of claim 18 wherein said effective amount is administered daily for a period of at least 7 days.
32 . The method of claim 18 wherein said effective amount is administered daily for a period of at least 2 weeks.
33 . The method of claim 18 wherein said effective amount is administered daily for a period of at least 4 weeks.
34 . The method of claim 18 wherein said effective amount is delivered orally.
35 . A method of inhibiting production of one or more cytokines in a mammal comprising administering to a mammal in need thereof an effective amount of a compound selected from the group consisting of pharmaceutically acceptable salts of:
1-[[1-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3methylbutanoyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine; trans-1-[[1-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3-phenylpropenoyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine; 1-[[1-[[N-[[4-(4-hydroxy-3-carboxyphenylazo) phenyl] sulfonil]-N-phenylamino] acetyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine [N-[4-(4-hydroxy-3-carboxyphenylazo) benzoyl]-N-[4-(1H-2-methylimidazole [4,5-c]pyridylmethyl) phenylsulfonyl]-L-leucine ethyl ester; [N-[4-(4-hydroxy-3-carboxyphenylazo) benzyl]-N-[4-(1H-2-methylimidazole [4,5-c]pyridylmethyl) phenylsulfonyl]-L-leucine ethyl ester; [N-[4-(4-hydroxy-3-carboxyphenylazo) benzyl]-N-[(S)-1-isobutyl-ethoxyethyl]-N-[4-(1H-2-mcthylimidazole [4,5-c]pyridylmethyl) phenylsulfonamide; cis- 1-[[1-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3-phenylpropenoyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine; and (Z)-2-hydroxy-5-[[4-[3-[4-[(2-methyl- 1H-imidazo[4,5-c]pyridin- 1-yl)methyl]-1-piperidinyl]-3-oxo-1-phenyl-1-propenyl]phenyl]azo] benzoic acid; including pharmaceutically acceptable solvates thereof.
36 . The method of claim 35 wherein said compound is 1-[[1-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3methylbutanoyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine sodium salt or pharmaceutically acceptable solvates thereof.
37 . The method of claim 35 wherein said compound is trans-1-[[l-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3-phenylpropenoyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine sodium salt or pharmaceutically acceptable solvates thereof.
38 . The method of claim 35 wherein said compound is 1-[[1-[[N-[[4-(4-hydroxy-3-carboxyphenylazo) phenyl] sulfonil]-N-phenylamino] acetyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine sodium salt or pharmaceutically acceptable solvates thereof.
39 . The method of claim 35 wherein said compound is [N-[4-(4-hydroxy-3-carboxyphenylazo) benzoyl]-N-[4-(1H-2-methylimidazole [4,5-c]pyridylmethyl) phenylsulfonyl]-L-leucine ethyl ester sodium salt or pharmaceutically acceptable solvates thereof.
40 . The method of claim 35 wherein said compound is [N-[4-(4-hydroxy-3-carboxyphenylazo) benzyl]-N-[4-(1H-2-methylimidazole [4,5-c]pyridylmethyl) phenylsulfonyl]-L-leucine ethyl ester sodium salt or pharmaceutically acceptable solvates thereof.
41 . The method of claim 35 wherein said compound is [N-[4-(4-hydroxy-3-carboxyphenylazo) benzyl]-N-[(S)-1-isobutyl-ethoxyethyl]-N-[4-(1H-2-methylimidazole [4,5-c]pyridylmethyl) phenylsulfonamide sodium salt or pharmaceutically acceptable solvates thereof.
42 . The method of claim 35 wherein said compound is cis-1-[[1-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3-phenylpropenoyl]-4-piperidyl] methyl]- 1H-2-methylimidazole [4,5-c]pyridine sodium salt or pharmaceutically acceptable solvates thereof.
43 . The method of claim 35 wherein said compound is (Z)-2-hydroxy-5-[[4-[3-[4-[(2-methyl- 1H-imidazo[4,5-c]pyridin- 1-yl)methyl]- 1 -piperidinyl]-3-oxo- 1-phenyl-1-propenyl]phenyl]azo] benzoic acid sodium salt or pharmaceutically acceptable solvates thereof.
44 . The method of claim 35 wherein said one or more cytokines includes interleukin-8 or tumor necrosis factor-α.
45 . The method of claim 35 wherein said production of one or more cytokines is caused by inflammatory bowel disease, including one or more of chronic gastrointestinal inflammation, colitis, ulcerative colitis or Crohn's disease.
46 . The method of claim 35 wherein said effective amount falls in the range of about 10 mg/kg to about 10,000 mg/kg.
47 . The method of claim 35 wherein said effective amount falls in the range of about 25 mg/kg to about 100 mg/kg.
48 . The method of claim 35 wherein said effective amount is administered at least daily, optionally in two or more divided doses.
49 . The method of claim 35 wherein said effective amount is administered daily for a period of at least 7 days.
50 . The method of claim 35 wherein said effective amount is administered daily for a period of at least 2 weeks.
51 . The method of claim 35 wherein said effective amount is administered daily for a period of at least 4 weeks.
52 . The method of claim 35 wherein said effective amount is delivered orally.Join the waitlist — get patent alerts
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